From the physiology of the kidney, it is generally known that it is the task of a healthy kidney to excrete end products of the metabolism as so-called “urinary substances” and toxins, so-called “uremic toxins” from the body via the urine. The kidney removes a broad spectrum of substances of different molecular masses. An overview of uremic toxins has been published by Vanholder et al. in 2003. [see Vanholder et al., Kidney International, 63 (2003) 1934-1943]. The uremic toxins are essentially divided into three classes on the basis of their molecular masses:
A) Low molecular mass toxins having a molecular mass of <500 g/mol;
B) toxins having an average molecular mass, also known as “mean molecules”, which have a molecular mass between 500 and 12,000 g/mol. For example, the medium molecules include β2-microglobulin (11800 g/mol).
C) The third class of uremic toxins are molecules with a molecular mass of >12,000 g/mol.
In addition, a distinction is made regarding the water solubility of the uremic toxins. Examples of highly water-soluble uremic toxins with a low molecular mass are urea, creatinine, oxalates, guanidine and uric acid.
Examples of poorly water-soluble uremic toxins are p-cresol, indoxyl sulfate, phenol, hippuric acid and homocysteine. These uremic toxins are mainly present in the serum in the form of being bound to proteins.
In healthy individuals, uremic toxins are excreted via the kidneys with urine. In chronic kidney failure, however, these toxins remain in the patient's blood and must be removed by hemodialysis or peritoneal dialysis.
While the removal of water-soluble toxins such as urea or creatinine with hemodialysis is very well possible, the removal of poorly water-soluble hydrophobic uremic toxins by hemodialysis is extremely difficult due to protein binding, since protein-bound uremic toxins are only accessible via the chemical equilibrium of the toxin-protein complex with free toxin in the blood plasma of hemodialysis, the equilibrium being strongly on the side of the complex. This means that the major part of uremic toxins is bound to proteins, while only a small portion is dissolved in the blood plasma and only these free uremic toxins can be dialyzed.
Further studies on the physiological chemistry of protein-bound uremic toxins have shown that human serum albumin acts as a binding partner of hydrophobic uremic toxins and thus toxin-albumin complexes form in the blood of the patient.
Albumin is retained by common dialysis membranes due to its molecular mass of approx. 65,000 g/mol. Albumin is therefore not removed by hemodialysis. This means that only the free, dissolved and very small proportion of uremic toxins can be removed from the patient's blood. After the removal of this small free portion, the balance between albumin-bound and free uremic toxins is restored.
Theoretically, this rebalancing could remove a significant proportion of the free uremic toxins by continuous dialysis. However, the association constants of the toxin-albumin complex as well as an insufficiently practicable dialysis time are in conflict with this.
For a long time now, there has therefore been a need for dialysis methods that are capable of effectively removing protein-bound uremic toxins from the blood of patients with chronic kidney failure or chronic intense renal insufficiency.